1. Field of the Invention
The present invention relates to an HNF-1 α gene including a novel single-nucleotide polymorphism and a protein encoded by the HNF-1 α gene, a polynucleotide associated with MODY3 diabetes based on the HNF-1 α gene, a microarray and diagnostic kit including the polynucleotide, and a method for diagnosis of MODY3 diabetes.
2. Description of the Related Art
The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor nucleic acid sequences [Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)]. The variant forms may confer an evolutionary advantage or disadvantage, relative to a progenitor form, or may be neutral. In some instances, a variant form confers a lethal disadvantage and is not transmitted to subsequent generations of the organism. In other instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of most members of the species and effectively becomes the progenitor form. In many instances, both progenitor and variant form(s) survive and co-exist in a species population. The coexistence of multiple forms of a sequence gives rise to polymorphisms.
Several different types of polymorphisms have been known, including restriction fragment length polymorphisms (RFLPs), short tandem repeats (STRs), variable number tandem repeats (VNTRs), and single-nucleotide polymorphisms (SNPs). Among them, SNPs take the form of single-nucleotide variations between individuals of the same species. When SNPs occur in protein coding sequences, any one of the polymorphic forms may give rise to the expression of a defective or a variant protein. On the other hand, when SNPs occur in non-coding sequences, some of these polymorphisms may result in the expression of defective or variant proteins (e.g., as a result of defective splicing). Other SNPs have no phenotypic effects.
It is known that human SNPs occur at a frequency of 1 in about 1,000 bp. When such SNPs induce a phenotypic expression such as a disease, polynucleotides containing the SNPs can be used as primers or probes for diagnosis of a disease. Monoclonal antibodies specifically binding with the SNPs can also be used in diagnosis of a disease. Such SNPs can be detected by an analytic method such as polymerase chain reaction (PCR), sequencing, hybridization, and single-strand conformation polymorphism (SSCP).
It is known that 90-95% of total diabetes patients suffer type II diabetes mellitus. Type II diabetes mellitus is a disorder which is developed in persons who abnormally produce insulin or have low sensitivity to insulin, thereby resulting in large change in blood glucose level. When disorder of insulin secretion leads to the condition of type II diabetes mellitus, blood glucose cannot be transferred to body cells, which renders the conversion of food into energy difficult. It is known that a genetic cause has a role in type II diabetes mellitus. Other risk factors of type II diabetes mellitus are age over 45, familial history of diabetes mellitus, obesity, hypertension, and high cholesterol level. Currently, diagnosis of diabetes mellitus is mainly made by measuring a pathological phenotypic change, i.e., blood glucose level, using fasting blood glucose (FSB) test, oral glucose tolerance test (OGTT), and the like. When diagnosis of type II diabetes mellitus is made, type II diabetes mellitus can be prevented or its onset can be delayed by exercise, special diet, body weight control, drug therapy, and the like. In this regard, it can be said that type II diabetes mellitus is a disease in which early diagnosis is highly desirable.
MODY3 is a type of the maturity-onset diabetes of the young which is one of type II diabetes mellitus. It is estimated that MODY3 is responsible for 10-30% of type II diabetes mellitus. It is known that MODY3 is caused by disorder of HNF-1 α gene (also called as “MODY3 gene”). Millenium Pharmaceuticals Inc. reported that diagnosis and prognosis of type II diabetes mellitus can be made based on genotypic variations present on HNF1 gene [PR newswire, Sep. 1, 1998]. Even though there are reports about some genes associated with type II diabetes mellitus, researches into the incidence of type II diabetes mellitus have been focused on specific genes of some chromosomes in specific populations. For this reason, research results may vary according to human species. Furthermore, all causative genes responsible for MODY3 diabetes have not yet been identified. Diagnosis of MODY3 diabetes by such a molecular biological technique is now uncommon. In addition, early diagnosis before incidence of MODY3 diabetes is currently unavailable. Therefore, there is an increasing need to find new SNPs highly associated with MODY3 diabetes and related genes that are found in whole human genomes and to make early diagnosis of MODY3 diabetes using the SNPs and the related genes.